Biased pharmacological modulators provide potential therapeutic benefits, including greater pharmacodynamic specificity, increased efficiency and reduced adverse effects. Therefore, the identification of such modulators as drug candidates is highly desirable. Currently, attention was mainly paid to biased signaling modulators targeting G protein-coupled receptors (GPCRs). The biased signaling modulation of non-GPCR receptors has yet to be exploited. Toll-like receptor 4 (TLR4) is one such non-GPCR receptor, which involves MyD88-dependent and TRIF-dependent signaling pathways. Moreover, the dysregulation of TLR4 contributes to numerous diseases, which highlights the importance of biased modulator development targeting TLR4. In this review, we aim to provide an overview of the recent progress in the discovery of biased modulators of TLR4. The challenges and methods for the discovery of TLR4 biased modulators are also outlined. Small molecules biasedly modulating the TLR4 signaling axis not only provide probes to fine-tune receptor conformation and signaling but also provide an opportunity to identify promising drug candidates. The discovery of biased modulators of TLR4 would provide insight for the future development of biased modulators for other non-GPCR receptors.
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